NM_021116.4:c.1450-5G>T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_021116.4(ADCY1):​c.1450-5G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.012 in 1,613,326 control chromosomes in the GnomAD database, including 169 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.011 ( 16 hom., cov: 32)
Exomes 𝑓: 0.012 ( 153 hom. )

Consequence

ADCY1
NM_021116.4 splice_region, intron

Scores

2
Splicing: ADA: 0.00003212
2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -3.37
Variant links:
Genes affected
ADCY1 (HGNC:232): (adenylate cyclase 1) This gene encodes a member of the of adenylate cyclase gene family that is primarily expressed in the brain. This protein is regulated by calcium/calmodulin concentration and may be involved in brain development. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.79).
BP6
Variant 7-45662054-G-T is Benign according to our data. Variant chr7-45662054-G-T is described in ClinVar as [Benign]. Clinvar id is 517524.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0121 (17612/1461070) while in subpopulation MID AF= 0.0222 (128/5758). AF 95% confidence interval is 0.0191. There are 153 homozygotes in gnomad4_exome. There are 8738 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 16 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ADCY1NM_021116.4 linkc.1450-5G>T splice_region_variant, intron_variant Intron 7 of 19 ENST00000297323.12 NP_066939.1
ADCY1NM_001281768.2 linkc.775-5G>T splice_region_variant, intron_variant Intron 8 of 9 NP_001268697.1
ADCY1XM_005249584.4 linkc.1450-5G>T splice_region_variant, intron_variant Intron 7 of 18 XP_005249641.1
ADCY1XM_005249585.3 linkc.1450-5G>T splice_region_variant, intron_variant Intron 7 of 8 XP_005249642.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ADCY1ENST00000297323.12 linkc.1450-5G>T splice_region_variant, intron_variant Intron 7 of 19 1 NM_021116.4 ENSP00000297323.7 Q08828
ADCY1ENST00000432715.5 linkc.775-5G>T splice_region_variant, intron_variant Intron 8 of 9 2 ENSP00000392721.1 C9J1J0
ADCY1ENST00000621543.1 linkc.775-5G>T splice_region_variant, intron_variant Intron 7 of 8 5 ENSP00000479770.1 C9J1J0
ADCY1ENST00000646653.1 linkn.391-5G>T splice_region_variant, intron_variant Intron 3 of 7

Frequencies

GnomAD3 genomes
AF:
0.0115
AC:
1747
AN:
152138
Hom.:
16
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00719
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0117
Gnomad ASJ
AF:
0.0501
Gnomad EAS
AF:
0.000192
Gnomad SAS
AF:
0.00498
Gnomad FIN
AF:
0.0116
Gnomad MID
AF:
0.0285
Gnomad NFE
AF:
0.0133
Gnomad OTH
AF:
0.0167
GnomAD3 exomes
AF:
0.0126
AC:
3152
AN:
250766
Hom.:
42
AF XY:
0.0125
AC XY:
1699
AN XY:
135474
show subpopulations
Gnomad AFR exome
AF:
0.00868
Gnomad AMR exome
AF:
0.0105
Gnomad ASJ exome
AF:
0.0473
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.00716
Gnomad FIN exome
AF:
0.0123
Gnomad NFE exome
AF:
0.0138
Gnomad OTH exome
AF:
0.0196
GnomAD4 exome
AF:
0.0121
AC:
17612
AN:
1461070
Hom.:
153
Cov.:
31
AF XY:
0.0120
AC XY:
8738
AN XY:
726768
show subpopulations
Gnomad4 AFR exome
AF:
0.00780
Gnomad4 AMR exome
AF:
0.0105
Gnomad4 ASJ exome
AF:
0.0452
Gnomad4 EAS exome
AF:
0.000101
Gnomad4 SAS exome
AF:
0.00715
Gnomad4 FIN exome
AF:
0.0109
Gnomad4 NFE exome
AF:
0.0122
Gnomad4 OTH exome
AF:
0.0143
GnomAD4 genome
AF:
0.0115
AC:
1745
AN:
152256
Hom.:
16
Cov.:
32
AF XY:
0.0118
AC XY:
882
AN XY:
74442
show subpopulations
Gnomad4 AFR
AF:
0.00715
Gnomad4 AMR
AF:
0.0117
Gnomad4 ASJ
AF:
0.0501
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00499
Gnomad4 FIN
AF:
0.0116
Gnomad4 NFE
AF:
0.0133
Gnomad4 OTH
AF:
0.0166
Alfa
AF:
0.0152
Hom.:
9
Bravo
AF:
0.0115
Asia WGS
AF:
0.00289
AC:
10
AN:
3478
EpiCase
AF:
0.0165
EpiControl
AF:
0.0175

ClinVar

Significance: Benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:3
Aug 05, 2019
Athena Diagnostics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 10, 2020
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 16, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not specified Benign:1
Aug 23, 2017
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

c.1450-5G>T in intron 7 of ADCY1: This variant is not expected to have clinical significance because it has been identified in 1.66% (1102/66292) of European ch romosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute. org; dbSNP rs77524127). -

ADCY1-related disorder Benign:1
Jun 20, 2019
PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.79
CADD
Benign
0.073
DANN
Benign
0.61

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.000032
dbscSNV1_RF
Benign
0.0060
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs77524127; hg19: chr7-45701653; API